Method for the treatment of acne using compositions comprising 0.3% by weight of 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid

ABSTRACT

Dermatological disorders having an inflammatory or proliferative component, notably common acne, are treated with topically applicable pharmaceutical compositions containing about 0.3% by weight of 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthanoic acid (adapalene) or salt thereof, formulated into pharmaceutically acceptable media therefor, advantageously formulated into topically applicable gels, preferably aqueous gels, creams, lotions or solutions.

CROSS-REFERENCE TO EARLIER APPLICATIONS

This application is a continuation of Ser. No. 12/772,861 filed May 3,2010, now allowed, which is a division of U.S. application Ser. No.11/494,693, filed Jul. 28, 2006, now U.S. Pat. No. 7,737,181, which is acontinuation-in-part of U.S. application Ser. No. 10/937,612, filed Sep.10, 2004, now U.S. Pat. No. 7,579,377, which is a continuation ofPCT/EP03/03246 filed Mar. 12, 2003 and designating the United States(published in English on Sep. 18, 2003 as WO 03/075908 A1), claimingbenefit of U.S. Provisional Application No. 60/370,223, filed Apr. 8,2002, and also claiming foreign priority under 35 U.S.C. §119 ofApplication No. 02/03070 filed in France on Mar. 12, 2002, each of theabove applications being hereby expressly incorporated by reference inits entirety and each being assigned to the assignee hereof.

BACKGROUND OF THE INVENTION

1. Technical Field of the Invention

The present invention relates to novel pharmaceutical compositionscomprising about 0.3% by weigh of6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthanoic acid, the chemicalstructure of which is as follows:

-   -   in particular dermatological compositions, for the treatment of        dermatological ailments, disorders, conditions or afflictions        having an inflammatory or proliferative component.

2. Description of Background and/or Related and/or Prior Art

6-[3-(1-Adamantyl)-4-methoxyphenyl]-2-naphthanoic acid (hereinafterreferred to as adapalene) is a retinoid derived from naphthoic acid,having anti-inflammatory properties. This molecule has been the subjectof development for the topical treatment of common acne and dermatosessensitive to retinoids.

Adapalene is described in EP-0,199,636, and a process for synthesizingsame is described in EP-0,358,574, both assigned to the assignee hereof.

The assignee hereof markets adapalene formulated at a weightconcentration of 0.1% in the form of an alcoholic lotion, an aqueous geland a cream. These compositions are suited for the treatment of acne.

SUMMARY OF THE INVENTION

Novel pharmaceutical compositions have now been developed containingadapalene at a weight concentration on the order of or about 0.3%,formulated into pharmaceutically acceptable media therefor, suited forthe treatment (regime or regimen) of dermatological ailments, conditionsor afflictions having an inflammatory or proliferative component.Specifically, it has now surprisingly been shown that, in addition toexhibiting better therapeutic efficacy compared to known compositions,the compositions according to the invention exhibit good tolerance,comparable to those of the known compositions with a lower concentrationof active principle.

The results regarding tolerance observed in trials relating tophoto-damaged skin (indication “photodamage”), obtained on individualson average 65 years old, could not be exploited in the context of thepresent invention. Specifically, as regards use of adapalene on youngindividuals (in particular regarding acne with populations of teenagersor young adults), the skin exhibits very different physiopathologicalcharacteristics (presence of many lesions, in particular inflammatorylesions, modifying skin permeability, hypercornification of thefollicular channel, immuno response, bacterial colonization of the skin(P. acnes), sebaceous hyperplasia with hyperseborrhea).

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1-3 are graphs illustrating the effectiveness of thedermatological compositions of the present invention versus comparativecompositions and controls.

DETAILED DESCRIPTION OF BEST MODE AND SPECIFIC/PREFERRED EMBODIMENTS OFTHE INVENTION

Thus, the present invention features pharmaceutical compositionscomprising about 0.3% by weight of adapalene(6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthanoic acid) relative to thetotal weight of the composition, or salts thereof, preferably in theform of aqueous gels. Such compositions are suited for the treatment(regime or regimen) of dermatological ailments, disorders or conditionshaving an inflammatory or proliferative component.

The term “adapalene salts” is intended to mean the salts formed with apharmaceutically acceptable base, in particular organic bases such assodium hydroxide, potassium hydroxide and aqueous ammonia, or organicbases such as lysine, arginine or N-methylglucamine.

The term “adapalene salts” is also intended to mean the salts formedwith a pharmaceutically acceptable base, in particular in organic basessuch as sodium hydroxide, potassium hydroxide and aqueous amonia, ororganic bases such as lysine, arginine or N-methylglucamine.

The term “adapalene salts” is also intended to mean the salts formedwith fatty amines such as dioctylamine and stearylamine.

The pharmaceutical compositions according to the invention arepreferably applied topically.

Topically, the pharmaceutical compositions according to the inventionare more particularly suited for treatment of the skin and the mucousmembranes, and may be in the form of ointments, creams, milks, pomades,powders, impregnated pads, solutions, gels, sprays, lotions orsuspensions. They may also be in the form of suspensions of microspheresor nanospheres or of lipid or polymeric vesicles, or of polymericpatches and hydrogels for controlled release. These compositions fortopical application may be in anhydrous form, in aqueous form or in theform of an emulsion.

In a preferred embodiment of the invention, the pharmaceuticalcompositions according to the invention are in the form of a gel,preferably aqueous, a cream, a lotion or a solution.

Accordingly, this invention also features pharmaceutical compositionscomprising about 0.3% by weight of adapalene(6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthanoic acid) relative to thetotal weight of the composition, or salt thereof, formulated as creams.

This invention also features pharmaceutical compositions comprisingabout 0.3% by weight of adapalene(6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthanoic acid) relative to thetotal weight of the composition, or salt thereof, formulated as lotions.

By “lotion” is intended a fluid emulsion of water-in-oil or oil-in-watertype. Preferably, the lotions according to the invention do not compriseany alcohol, but may comprise at least one glycol; consequently, theyare not alcoholic, but preferably glycolic.

Another embodiment of the invention features pharmaceutical compositionscomprising about 0.3% by weight of adapalene(6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthanoic acid) relative to thetotal weight of the composition, or salt thereof, formulated assolutions or spray solutions.

By “solution” is intended to a liquid composition at ambient temperature(20-30°) and comprises a single phase. Such compositions are preferablyalcoholic or may comprise at least one glycol or lipophilic component.

In particular, the pharmaceutical composition may be an aqueous gelcomprising at least one ingredient selected from among:

Carbomers, for example Carbopol 980 NF marketed by NOVEON;

polymeric emulsifying agents such as PEMULEN (crosspolymersacrylates/C10-30 alkyl acrylates, for example, PEMULEN TR1, PEMULEN TR2,CARBOPOL 1342, CARBOPOL 1382, Carbopol 981 or carbopol Ultrez marketedby the company NOVEON);

polysaccharidic biopolymers such as xanthan gum (for example, Keltrol Tand Xantural 180 marketed by the company Kelco);

gums such as caroub gum, guar gum;

alginates;

modified celluloses such as hydroxyethylcellulose, methylcellulose,hydroxypropylcellulose (for example Natrosol HHX 250 marketed by thecompany Aqualon), hydroxypropylmethylcellulose andcarboxymethylcellulose;

starch derived products such as Structure XL marketed by the companyNational Starch;

a mix of polysorbate 80 and isohexadecane and acrylamide/sodiumacryloyldimethyltaurate (such as Simulgel 600); and

humectants or pro-penetrant agents such as propylene glycol orequivalent, for example, glycerin and sorbitol, for example, alkylensand polyalkylenes glycols (C1 to CE) such as ethylene glycol,polyethylene glycol (2 to 20 monomers), propylene glycol, dipropyleneglycol, butylene glycol, pentylene glycol, hexylene glycol. These lattercould be oxyethylened or not (2 to 50 QE). Glycol ethers are alsorepresentative such as ethoxydiglycol, diethylene glycol monoethylether(tradename transcutol HP by GATTEFOSSE company), dipelargonate propyleneglycol, propylene glycol laurate (tradename Lauroglycol by GATTEFOSSEcompany), Propylene glycol dicaprate dicaprylate (tradename Estol 1526by UNIQEMA company); and

the pro-penetrants such as fatty esters family, fatty acids or fattyalcohols or alcohols, for example, ethanol, dimethyl isosorbide(tradename Arlasolve DMI by UNIQEMA company), pyrrolidone methyl(tradename Pharmasolve by ISP company), oleic acid (tradename Oléine V2by Stéarinerie Dubois company), PEG-8 capric/caprylic glycerids(tradename LAERASOL by GATTEFOSSE company) and oleic alcohol (tradenameHD EUTANOL V PH by COGNIS company).

In particular, the pharmaceutical composition may be a cream comprisingat least one ingredient selected from among:

mineral oils such as perhydrosqualene;

silicone oils such as cyclomethicone;

siliconed oily components such as siliconed fatty components;

non-siliconed fatty components such as vegetable, mineral, animal orsynthetic oils;

tensioactive agents or emulsifying agents, preferably such as PEG-20methyl glucose sequistearate or Methyl glucose sesquistearate.

Among the non-siliconed oily components, the common oils arerepresentative such as paraffin oil, Vaseline (or petroleum jelly),almond oil, perhydrosqualene, apricot oil, wheat germs oil, sweet almondoil, calophyllum oil, palm oil, castor oil, avocado oil, jojoba oil,olive oil or cerales germs oil; fatty acids esters or fatty alcoholsesters such as dodecyl octyl octanoates, alcohols or polyalcoholsdecanoates or ricinoleates; fatty acids triglycerides; glycerides;hydrogenated polyisobutene, solid at 25° C. hydrogenated oils;lanolines; solid at 25° C. fatty esters; adipate diisopropyl (tradenameCrodamol DA by Croda company), PPG 15 stearyl ether (tradename Arlamol Eby UNIQEMA company), octyl dodecanol (tradename Eutanol G by COGNIScompany), Caprilic/capric triglycerides (tradename Miglyol 8I2N by SPCIcompany), C12-C15 alkyl benzoate (tradename Tegosoft TN by Degussacompany).

As tensioactive agents or as emulsifying agents, several components arerepresentative selected from among PEG-20 methyl glucose sequistearate(tradename GLUCAMATE SSE 20 by Amerchol company) or Methyl glucosesesquistearate (tradename GLUCATE SS by Amerchol company), unsaturatedor saturated fatty acids esters, oleic acid or isostearic acid such aspolyglycerin and isostearic acid esters (tradename LAMEFORM TGI bySIDOBRE-SINNOVA HENKEL company), sorbitan isostearate (tradename ARLACEL987 by UNIQEMA company), sorbitan sesquioleate (tradename ARLACEL 83 byUNIQEMA company), sorbitan laurate (tradename SPAN 20 by UNIQEMAcompany), glycol and isostearic acid esters such as PEG-6 isostearate(tradename OLEPAL ISOSTEARIQUE by GATTEFOSSE company), sorbitol andoleic acid esters such as polysorbates (tradename TWEEN by UNIQEMAcompany), fatty alcohols ethers such as oleic acid and particularlyglycol and oleic acid esters such as oleths (tradename BRIJ by UNIQEMAcompany), oxyethylenated sorbitan monostearate, fatty alcohols such asstearylic alcohol or cetylic alcohol and particularly selected fromamong macrogol 21 stearylether (tradename BRIJ 721 by UNIQEMA company),macrogol 2 stearylether (tradename BRIJ 72P by UNIQEMA company),glyceryl/PEG 100 stearate (tradename Arlacel 165FL by UNIQEMA company),ceteareth 20 (tradename Eumulgin B2 by COGNIS company), PEG-6 and PEG 32palmitostearate (tradename TEFOSE 1500 by GATTEFOSSE company).

In particular, the pharmaceutical composition may be a lotion comprisingat least one ingredient selected from among:

humectant agent or pro-penetrant agent such as propylene glycol (orequivalent such as glycerin and sorbitol), polyethylene glycol, PEG400;

mineral oils such as perhydrosqualene as previously described;

lipophilic components such as Caprilic/capric triglycerides aspreviously described;

emulsifying agents such as described, for example, PEG-20 methyl glucosesequistearate and methyl glucose sequistearate.

Also in particular, the pharmaceutical composition may be a solution ora spray solution comprising alcohol and at least one ingredient selectedfrom among:

humectant agent or pro-penetrant agent as described previously andpreferably such as propylene glycol, polyethylene glycol, or PEG400;

a lipophilic component, such as siliconed or non-siliconed fattycomponents or Caprilic/capric triglycerides.

Preferably in the form of gel, the composition has of following formula:

Adapalene 3 mg Carbomer 940 (Carbopol 980 NF) 11 mg  Disodium edetate 1mg Methyl paraben 2 mg Poloxamer 124 2 mg Propylene glycol 40 mg  Sodiumhydroxide: amount required to obtain a pH 5.0 +/− 0.3 Purified waterq.s. 1 g

The pharmaceutical compositions according to the invention may alsocomprise inert additives or combinations thereof, such as:

wetting agents;

flavor enhancers;

preservatives such as para-hydroxybenzoic acid esters;

stabilizers;

moisture regulators;

pH regulators;

osmotic pressure modifiers;

emulsifiers;

UV-A and UV-B screening agents; and

antioxidants, such as α-tocopherol, butylhydroxyanisole orbutylhydroxytoluene, superoxide dismutase, ubiquinol or certain metalchelating agents.

Of course, those skilled in the art will take care to select theoptional compound(s) to be added to these compositions in such a waythat the advantageous properties intrinsically associated with thepresent invention are not, or are not substantially, adversely affectedby the envisaged addition.

The pharmaceutical compositions according to the invention are suitedfor the treatment of dermatological ailments, conditions and afflictionshaving an inflammatory or proliferative component, selected from thegroup consisting of:

common acne, comedones, polymorphous acne, nodulocystic acne, acneconglobata, secondary acne such as solar, drug-related or occupationalacne;

widespread and/or severe forms of psoriasis, ichtyoses and ichtyosiformstates;

Darier's disease;

actinic keratoses;

palmo plantar keratoderma and keratosis pilaris;

leucoplasias and leucoplasiform states, lichen planus;

any benign or malignant, severe and extensive dermatologicalpreparations.

The compositions according to the invention are particularly suitablefor the treatment of acne, such as common acne, and in particular forthe treatment of common acne of moderate to moderately severe intensity.

Various formulations of compositions comprising 0.3% of adapalene willnow be given, it being understood that same are intended only asillustrative and in nowise limitative. Also given are results showingthe therapeutic effects of the compositions according to the inventionand the good tolerance to same by the treated patients.

In said examples to follow, all parts and percentages are given byweight, unless otherwise indicated.

EXAMPLE 1 Formulation for Topical Administration

In this example, various specific topical formulations comprising 0.3%of adapalene are illustrated.

The adapalene of the present example was obtained from the companySylachim.

(a) Cream:

Adapalene 3 mg Carbomer 934 (BF Goodrich Carbopol 974) 4.5 mg Disodiumedetate 1 mg PEG 20 methyl glucose sesquistearate 35 mg Methyl glucosesesquistearate 35 mg Glycerol 30 mg Methyl paraben 2 mg Cyclomethicone130 mg Perhydrosqualene 60 mg Phenoxyethanol 5 mg Propyl paraben 1 mgSodium hydroxide quantity required for pH 6.5 +/− 0.3 Purified waterq.s. 1 g

(b) Alcoholic Solution:

Adapalene 3 mg PEG 400 700 mg Ethanol q.s. 1 mg

(c) Lotion:

Adapalene 0.30 Methyl paraben 0.15 Simulgel 600 PHA 1.00 Steareth 213.00 Glyceryl and PEG 100 stearate 3.00 Disodium edetate 0.10 Propylparaben 0.05 Perhydrosqualene 5.00 Cetearyl isonananoate 5.00 SodiumHydroxide 10% m/m q.s. pH 5.5 ± 0.5 Purified water q.s. 100

(d) Lotion:

Disodium EDTA 0.1 Methyl paraben 0.2 Glycerine 7.0 Carbopol 981 NF 0.15Propyl paraben 0.1 Ceteareth 20 3.0 Stearyl alcohol 2.0 Caprilic/caprictriglycerides 7 Glyceryl and PEG 100 stearate 3.0 Cyclomethicone 5 6Poloxamer 124 0.2 Propylene glycol 4.0 Adapalene 0.3 Simulgel 600 PHA1.0 Solution aq. De NaOH 10% 0.4 Purified water q.s. 100

(e) Lotion:

EDTA disodium 0.1 Methyl paraben 0.2 Carbopol 980 NF 0.15 Carbapol 981NF 0.3 Glycerine 3.0 Phenoxyethanol 1.0 Propyl paraben 0.2 Methylglucose sesquistearate 1.0 PEG 20 methyl glucose sesquistearate 5.0Caprilic/capric triglycerides 6.0 Dimethicone 20 cst 1.0 Poloxamer 1240.2 Propylene glycol 4 Adapalene 0.3 Sodium hydroxide 10% (w/w) 0.8Purified water q.s. 100

(f) Aqueous Gel:

Adapalene 3 mg Carbomer 940 (Carbapol 980) 11 mg Disodium edetate 1 mgMethyl paraben 2 mg Poloxamer 124 2 mg Propylene glycol 40 mg Sodiumhydroxide: amount required to obtain a pH 5.0 +/− 0.3 Purified waterq.s. 1 g

(g) Aqueous Gel:

Adapalene 3 mg Xanthan gum 8 mg Hydroxypropylethylcellulose 10 mgDisodium edetate 1 mg Methyl paraben 2 mg Phenoxyethanol 10 mg Poloxamer124 2 mg Propylene glycol 40 mg Purified water q.s. 1 g

(h) Cream Gel:

Adapalene 3 mg Simulgel 600 PHA 20 mg Cetearyl isononanoate 100 mgDisodium edetate 1 mg Methyl paraben 2 mg Poloxamer 124 2 mg Propyleneglycol 40 mg Purified water q.s. 1 g

(i) Cream Gel:

Adapalene 3 mg Pemulen TR1 5 mg Mineral oil 120 mg Disodium edetate 1 mgMethyl paraben 2 mg Propyl paraben 1 mg Poloxamer 124 2 mg Propyleneglycol 40 mg Sodium hydroxide: amount required to obtain a pH 5.0 +/−0.3 Purified water q.s. 1 g

(j) Spray Solution: (% w/w)

Adapalene 0.3 Caprilic/capric triglycerides 50 N-methyl pyrrolidone 3Ethanol q.s. 100

EXAMPLE 2 Effectiveness of 0.3% Adapalene Gel and Comparison with 0.1%Adapalene Gel

Tests were carried out on a population consisting of patients sufferingfrom acne. In this population, three groups were differentiated; thefirst received a daily topical application of the 0.3% adapalene gel,the second a daily topical application of the 0.1% adapalene gel in thesame vehicle, and the third is a control group which receives a dailytopical application of the gel corresponding to the composition of thefirst two gels but containing no active agent.

FIGS. 1 to 3 provide the results obtained in terms of regression of thenumber of lesions according to their nature.

These observations lead to the following conclusions;

the 0.3% adapalene gel acts more rapidly than the 0.1% adapalene gel;specifically, from the fourth week of treatment, a difference is notedbetween the effectiveness of the 0.1% adapalene gel and the 0.3%adapalene gel;

the 0.3% adapalene gel produces a clearly greater therapeutic effectafter 8 weeks of treatment.

EXAMPLE 3 Tolerance Regarding the 0.3% Adapalene Gel

1. Measurement of the Plasma Concentration of Adapalene:

Eight individuals suffering from common acne of medium to moderatelysevere intensity are treated for 10 days with 2 g of 0.3% adapalene gelapplied daily over 1000 cm² of skin to be treated (face, chest andback).

Blood samples are taken on the days 1, 2, 4, 6, 8 and 10. During day 10,and following the final application, samples are taken at 1, 2, 6, 8,10, 12, 16 and 24 hours.

The plasma concentration of total adapalene (free and conjugated) inthese samples is determined using the following protocol:

enzymatic hydrolysis with a mixture of β-glucurodinase andarylsulfatase;

liquid-liquid extraction;

passage through HPLC (high performance liquid chromatography); and

then fluorometric detection.

This method makes it possible to detect a minimum concentration of 0.15ng/ml and permits quantification of the adapalene for a minimumconcentration of 0.25 ng/ml.

Conclusion:

The plasma concentrations of adapalene measured after 10 days oftreatment are very low and confirm the safety of daily use of the 0.3%adapalene gel.

2 a) Clinical Observation of the Side Effects Caused by TopicalAdministration of the 0.3% Adapalene Gel:

Two types of observation could be made:

firstly, monitoring of the patients treated within the framework ofpoint 1 of the present example 3 made it possible to note that toleranceto the 0.3% adapalene gel was good for all patients. They all showedsigns of dryness of the skin and of desquamation with a maximum on theseventh day of treatment, these symptoms then decrease up to the end ofthe treatment.

2 b) Furthermore, Reference May Also be Made to the Tests Described inExample 2 Above:

In parallel to the measurements of effectiveness, the experimentersrecorded the possible side effects caused, firstly, by topicalapplication of the 0.3% adapalene gel and those caused, secondly, byapplication of the 0.1% adapalene gel; finally, the same observationswere made on a control population to which a gel without activeprinciple was administered.

These observations are reported in the table below.

Local undesirable 0.3% adapalene 0.1% adapalene Vehicle gel effects gel(N = 70) gel (N = 70) (N = 74) Skin and secondary 31 (44.3%) 28 (40.0%)5 (6.8%) structures (nails, hair) Dry skin 16 (22.9%) 13 (18.6%) 2(2.7%) Erythema  8 (11.4%) 3 (4.3%) 0 (0.0%) Skin discomfort  8 (11.4%) 7 (10.0%) 0 (0.0%) Desquamation 6 (8.6%) 5 (7.1%) 0 (0.0%) Dermatitis 3(4.3%) 1 (1.4%) 0 (0.0%) Pruritus 3 (4.3%)  1 1.4%) 1 (1.4%) Irritantdermatitis 2 (2.9%)  7 (10.0%) 0 (0.0%) Local allergic reactions 1(1.4%) 0 (0.0%) 0 (0.0%) Pediculosis 1 (1.4%) 0 (0.0%) 0 (0.0%) Contactdermatitis 1 (1.4%) 0 (0.0%) 0 (0.0%) Insolation 1 (1.4%) 3 (4.3%) 1(1.4%) Burning sensation 1 (1.4%) 0 (0.0%) 0 (0.0%) Urticaria 1 (1.4%) 0(0.0%) 0 (0.0%) Infection 1 (1.4%) 0 (0.0%) 0 (0.0%) Excoriation 0(0.0%) 0 (0.0%) 1 (1.4%) Eczema 0 (0.0%) 0 (0.0%) 1 (1.4%) Oedema 0(0.0%) 1. (1.4%)  0 (0.0%)

From this table, it is noted that the occurrence of undesirable sideeffects is statistically the same for the two gels with the differentconcentrations of active agent. The intensity of the undesirable sideeffects is average, which leads to the conclusion that the two gels arewell-tolerated by the patients.

On the basis of these observations, it may be concluded that patientssuffering from common acne can be treated with 0.3% adapalene gel, suchan exposure to adapalene being described as weak or very weak underclinical conditions.

It therefore ensues from these various studies that a pharmaceuticalcomposition containing 0.3% of adapalene exhibits a benefit/risk ratiowhich makes it particularly suitable for the treatment of dermatologicalmaladies having an inflammatory or proliferative component, and inparticular, common acne.

Each patent, patent application, publication and literaturearticle/report cited or indicated herein is hereby expresslyincorporated by reference.

While the invention has been described in terms of various specific andpreferred embodiments, the skilled artisan will appreciate that variousmodifications, substitutions, omissions, and changes may be made withoutdeparting from the spirit thereof. Accordingly, it is intended that thescope of the present invention be limited solely by the scope of thefollowing claims, including equivalents thereof.

What is claimed is:
 1. A method for treating common acne, comedones,polymorphous acne, nodulocystic acne, acne conglobata, or secondary acneafflicting the skin of an individual in need of such treatment,comprising topically administering to said individual a topicallyapplicable pharmaceutical aqueous gel composition consisting essentiallyof an anti-acne effective amount of6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthanoic acid (adapalene) of0.3% by weight thereof, formulated into a topically applicable,pharmaceutically acceptable aqueous gel medium therefor, whereinadapalene is the only active anti-acne ingredient in the composition andwherein said aqueous gel medium comprises at least one ingredientselected from the group consisting of carbomers, polymeric emulsifyingagents, polysaccharidic biopolymers, gums, alginates, modifiedcelluloses, starch derived products, mix of polysorbate 80 andisohexadecane and acrylamide/sodium acryloyldimethyltaurate, andmixtures thereof.
 2. The method as defined by claim 1, wherein saidaqueous gel medium comprises: Carbomer, Disodium edetate, Methylparaben, Poloxamer 124, Propylene glycol, Sodium hydroxide, and Purifiedwater.
 3. The method as defined by claim 1, wherein said topicallyapplicable pharmaceutical aqueous gel composition consists essentiallyof: Adapalene 3 mg Carbomer 940 11 mg Disodium edetate 1 mg Methylparaben 2 mg Poloxamer 124 2 mg Propylene glycol 40 mg Sodium hydroxide:amount required to obtain a pH 5.0 +/− 0.3 and Purified water q.s. 1 g.


4. The method as defined by claim 1, wherein said aqueous gel mediumcomprises: Xanthan gum, Hydroxypropylethylcellulose, Disodium edetate,Methyl paraben, Phenoxyethanol, Poloxamer 124, Propylene glycol, andPurified water.
 5. The method as defined by claim 1, wherein saidtopically applicable pharmaceutical aqueous gel composition consistsessentially of: Adapalene 3 mg Xanthan gum 8 mgHydroxypropylethylcellulose 10 mg Disodium edetate 1 mg Methyl paraben 2mg Phenoxyethanol 10 mg Poloxamer 124 2 mg Propylene glycol 40 mgPurified water q.s. 1 g.


6. A method for treating common acne, comedones, polymorphous acne,nodulocystic acne, acne conglobata, or secondary acne afflicting theskin of an individual in need of such treatment, comprising topicallyadministering to said individual a topically applicable pharmaceuticalaqueous cream gel composition consisting essentially of an anti-acneeffective amount of 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthanoicacid (adapalene) of 0.3% by weight thereof, formulated into a topicallyapplicable, pharmaceutically acceptable aqueous cream gel mediumtherefor, wherein adapalene is the only active anti-acne ingredient inthe composition.
 7. The method as defined by claim 6, wherein saidaqueous cream gel medium comprises: Simulgel 600 PHA, Cetearylisononanoate, Disodium edetate, Methyl paraben, Poloxamer 124, Propyleneglycol, and Purified water.
 8. The method as defined by claim 6, whereinsaid topically applicable pharmaceutical aqueous cream gel compositionconsists essentially of: Adapalene 3 mg Simulgel 600 PHA 20 mg Cetearylisononanoate 100 mg Disodium edetate 1 mg Methyl paraben 2 mg Poloxamer124 2 mg Propylene glycol 40 mg Purified water q.s. 1 g.


9. The method as defined by claim 6, wherein said aqueous cream gelmedium comprises: Pemulen TR1, Mineral Oil, Disodium edetate, Methylparaben, Propyl paraben, Poloxamer 124, Propylene glycol, Sodiumhydroxide: amount required to obtain a pH 5.0+/−0.3, and Purified water.10. The method as defined by claim 6, wherein said topically applicablepharmaceutical aqueous cream gel composition consists essentially of:Adapalene 3 mg Pemulen TR1 5 mg Mineral oil 120 mg Disodium edetate 1 mgMethyl paraben 2 mg Propyl paraben 1 mg Poloxamer 124 2 mg Propyleneglycol 40 mg Sodium hydroxide: amount required to obtain a pH 5.0 +/−0.3 Purified water q.s. 1 g.


11. A method for treating common acne, comedones, polymorphous acne,nodulocystic acne, acne conglobata, or secondary acne afflicting theskin of an individual in need of such treatment, comprising topicallyadministering to said individual a topically applicable pharmaceuticalcream composition consisting essentially of an anti-acne effectiveamount of 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthanoic acid(adapalene) of 0.3% by weight thereof, formulated into a topicallyapplicable, pharmaceutically acceptable cream medium therefor, whereinadapalene is the only active anti-acne ingredient in the composition.12. The method as defined by claim 11, wherein said cream mediumcomprises at least one ingredient selected from the group consisting ofsilicone oils, siliconed oily substances, siliconed fatty substances,non-siliconed fatty substances, vegetable oils, mineral oils, animaloils and synthetic oils, and mixtures thereof.
 13. The method as definedby claim 12, wherein said cream medium comprises at least one ingredientselected from the group consisting of perhydrosqualene, cyclomethicone,PEG-20 methyl glucose sequistearate, methyl glucose sequistearate, andmixtures thereof.
 14. The method as defined by claim 11, wherein saidcream medium comprises: Carbomer 934 (BF Goodrich Carbopol 974),Disodium edetate, PEG 20 methyl glucose sesquistearate, Methyl glucosesesquistearate, Glycerol, Methyl paraben, Cyclomethicone,Perhydrosqualene, Phenoxyethanol, Propyl paraben, Sodium hydroxidequantity required for pH 6.5+/−0.3, and Purified water.
 15. The methodas defined by claim 11, wherein said topically applicable pharmaceuticalcream composition consists essentially of: Adapalene 3 mg Carbomer 934(B F Goodrich Carbopol 974) 4.5 mg   Disodium edetate 1 mg PEG 20 methylglucose sesquistearate 35 mg  Methyl glucose sesquistearate 5 mgGlycerol 30 mg  Methyl paraben 2 mg Cyclomethicone 130 mg Perhydrosqualene 60 mg  Phenoxyethanol 5 mg Propyl paraben 1 mg Sodiumhydroxide quantity required for pH 6.5 +/− 0.3 Purified water q.s. 1 g.


16. A method for treating common acne, comedones, polymorphous acne,nodulocystic acne, acne conglobata, or secondary acne afflicting theskin of an individual in need of such treatment, comprising topicallyadministering to said individual a topically applicable pharmaceuticalaqueous lotion composition consisting essentially of an anti-acneeffective amount of 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthanoicacid (adapalene) of 0.3% by weight thereof, formulated into a topicallyapplicable, pharmaceutically acceptable aqueous lotion medium therefor,wherein adapalene is the only active anti-acne ingredient in thecomposition.
 17. The method as defined by claim 16, wherein said aqueouslotion medium comprises at least one ingredient selected from the groupconsisting of humectant agent, pro-penetrant agent, propylene glycol,PEG400, mineral oils, lipophilic substances, caprilic/caprictriglycerides, emulsifying agent, and mixtures thereof.
 18. The methodas defined by claim 16, wherein said aqueous lotion medium comprises atleast one ingredient selected from the group consisting of propyleneglycol, glycerine, sorbitol, polyethylene glycol, mineral oils,perhydrosqualene, caprilic/capric triglycerides, PEG-20 methyl glucosesequistearate, methyl glucose sequistearate, and mixtures thereof. 19.The method as defined by claim 16, wherein said aqueous lotion mediumcomprises: Methyl paraben, Simulgel 600 PHA, Steareth 21, Glyceryl andPEG 100 stearate, Disodium edetate, Propyl paraben, Perhydrosqualene,Cetearyl isononanoate, Sodium Hydroxide 10% m/m, and Purified water. 20.The method as defined by claim 16, wherein said topically applicablepharmaceutical aqueous lotion composition consists essentially of: (%w/w) Adapalene 0.30 Methyl paraben 0.15 Simulgel 600 PHA 1.00 Steareth21 3.00 Glyceryl and PEG 100 stearate 3.00 Disodium edetate 0.10 Propylparaben 0.05 Perhydrosqualene 5.00 Cetearyl isononanoate 5.00 SodiumHydroxide 10% m/m q.s. pH 5, 5 ± 0.5 Purified water q.s.
 100.


21. The method as defined by claim 16, wherein said aqueous lotionmedium comprises: Disodium EDTA, Methyl paraben, Glycerine, Carbopol 981NF, Propyl paraben, Ceteareth 20, Stearyl alcohol, Caprilic/caprictriglycerides, Glyceryl and PEG 100 stearate, Cyclomethicone 5,Poloxamer 124, Propylene glycol, Simulgel 600 PHA, Solution aq. NaOH10%, and Purified water.
 22. The method as defined by claim 16, whereinsaid topically applicable pharmaceutical aqueous lotion compositionconsists essentially of: (% w/w) Disodium EDTA 0.1 Methyl paraben 0.2Glycerine 7.0 Carbopol 981 NF 0.15 Propyl paraben 0.1 Ceteareth 20 3.0Stearyl alcohol 2.0 Caprilic/capric triglycerides 7 Glyceryl and PEG 100stearate 3.0 Cyclomethicone 5 6 Poloxamer 124 0.2 Propylene glycol 4.0Adapalene 0.3 Simulgel 600 PHA 1.0 Solution aq. NaOH 10% 0.4 Purifiedwater q.s.
 100.


23. The method as defined by claim 16, wherein said aqueous lotionmedium comprises: EDTA disodium, Methyl paraben, Carbopol 980 NF,Carbopol 981 NF, Gylcerine, Phenoxyethanol, Propyl paraben, Methylglucose sesquistearate, PEG 20 methyl glucose sesquistearate,Caprilic/capric triglycerides, Dimethicone 20 cst, Poloxamer 124,Propylene glycol, Sodium Hydroxide 10% m/m, and Purified water.
 24. Themethod as defined by claim 16, wherein said topically applicablepharmaceutical aqueous lotion composition consists essentially of: (%w/w) Disodium EDTA 0.1 Methyl paraben 0.2 Glycerine 7.0 Carbopol 981 NF0.15 Propyl paraben 0.1 Ceteareth 20 3.0 Stearyl alcohol 2.0Caprilic/capric triglycerides 7 Glyceryl and PEG 100 stearate 3.0Cyclomethicone 5 6 Poloxamer 124 0.2 Propylene glycol 4.0 Adapalene 0.3Simulgel 600 PHA 1.0 Solution aq. NaOH 10% 0.4 Purified water q.s.
 100.


25. A method for treating common acne, comedones, polymorphous acne,nodulocystic acne, acne conglobata, or secondary acne afflicting theskin of an individual in need of such treatment, comprising topicallyadministering to said individual a topically applicable pharmaceuticalspray solution composition consisting essentially of an anti-acneeffective amount of 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthanoicacid (adapalene) of 0.3% by weight thereof, formulated into a topicallyapplicable, pharmaceutically acceptable spray solution medium therefor,said spray solution medium comprising caprilic/capric triglycerides,wherein adapalene is the only active anti-acne ingredient in thecomposition.
 26. The method as defined by claim 25, wherein said spraysolution medium further comprises at least one ingredient selected fromthe group consisting of humectant agent, pro-penetrant agent, propyleneglycol, polyethylene glycol, PEG400, a lipophilic substance, siliconedfatty substances, non-siliconed fatty substances, and mixtures thereof.27. The method as defined by claim 25, wherein said spray solutionmedium comprises: Caprilic/capric triglycerides, N-methylpyrrolidone,and Ethanol.
 28. The method as defined by claim 25, wherein saidtopically applicable pharmaceutical spray solution composition consistsessentially of: (% w/w) Adapalene 0.3 Caprilic/capric triglycerides 50N-methyl pyrrolidone 3 Ethanol q.s.
 100.


29. The method as defined by claim 1, wherein said aqueous gel mediumcomprises at least one inert additive selected from the group consistingof: wetting agents; flavor enhancers; preservatives; stabilizers;moisture regulators; pH regulators; osmotic pressure modifiers;emulsifiers; UV-A and UV-B screening agents; Antioxidants; andcombinations thereof.
 30. The method as defined by claim 6, wherein saidaqueous cream gel medium comprises at least one inert additive selectedfrom the group consisting of: wetting agents; flavor enhancers;preservatives; stabilizers; moisture regulators; pH regulators; osmoticpressure modifiers; emulsifiers; UV-A and UV-B screening agents;Antioxidants; and combinations thereof.
 31. The method as defined byclaim 11, wherein said cream medium comprises at least one inertadditive selected from the group consisting of: wetting agents; flavorenhancers; preservatives; stabilizers; moisture regulators; pHregulators; osmotic pressure modifiers; emulsifiers; UV-A and UV-Bscreening agents; Antioxidants; and combinations thereof.
 32. The methodas defined by claim 16, wherein said aqueous lotion medium comprises atleast one inert additive selected from the group consisting of: wettingagents; flavor enhancers; preservatives; stabilizers; moistureregulators; pH regulators; osmotic pressure modifiers; emulsifiers; UV-Aand UV-B screening agents; Antioxidants; and combinations thereof. 33.The method as defined by claim 25, wherein said spray solution mediumcomprises at least one inert additive selected from the group consistingof: wetting agents; flavor enhancers; preservatives; stabilizers;moisture regulators; pH regulators; osmotic pressure modifiers;emulsifiers; UV-A and UV-B screening agents; Antioxidants; andcombinations thereof.
 34. The method as defined by claim 16, whereinsaid topically applicable pharmaceutical aqueous lotion compositionconsists essentially of: (% w/w) EDTA disodium 0.1 Methyl paraben 0.2Carbopol 980 NF 0.15 Carbopol 981 NF 0.3 Gylcerine 3.0 Phenoxyethanol1.0 Propyl paraben 0.2 Methyl glucose sesquistearate 1.0 PEG 20 methylglucose sesquistearate 5.0 Caprilic/capric triglycerides 6.0 Dimethicone20 cst 1.0 Poloxamer 124 0.2 Propylene glycol 4 Adapalene 0.3 SodiumHydroxide 10% m/m 0.8 Purified water q.s.
 100.


35. The method as defined by claim 1, wherein said aqueous gel mediumcomprises at least one carbomer.
 36. The method as defined by claim 1,wherein said aqueous gel medium comprises carbomer 940.